Orally dissolving melatonin formulation with acidifying agent that renders melatonin soluble in saliva

ABSTRACT

A composition includes a pharmaceutical dosage form configured to dinsintegrate in saliva and maintain a pH of 4 or less within the saliva during the time the dosage form is dissolving therein. The dosage form includes a therapeutically effective amount of melatonin in a carrier matrix, a disintegrant, and a sufficient amount of acid to impart the pH to the saliva. The amount of disintegrant is sufficient to cause the dosage form to completely disintegrate in the saliva within ten minutes from contacting the saliva.

CROSS-REFERENCE TO RELATED APPLICATION

This claims the benefit of priority to U.S. provisional Application No.62/522,473, filed Jun. 20, 2017, which is incorporated by reference inits entirety.

FIELD

This relates to the field of orally dissolving pharmaceutical dosageforms and, more particularly, to those containing melatonin.

BACKGROUND

Melatonin is a naturally produced hormone that helps regulate the body'ssleep/wake cycles. The amount of melatonin the body produces depends onthe time of day. Endogenous melatonin levels start increasing in theevening, peak during the late night hours, and gradually startdecreasing in the early morning.

Melatonin is known to have many therapeutic benefits, especiallyassociated with sleep. It has been used to treat sleep problems such asinsomnia and jet lag. It has also been used to help patients re-programtheir circadian clocks to account for changes in light/dark cycles dueto time changes. It has also been proposed to act as an antioxidant.

Conventional oral melatonin treatments present several problems. Oraldosage forms have shown low and variable bioavailability. It can take along time for absorption into the plasma when administered via thegastrointestinal tract. This is partly due to the fact that melatoninmust first release from the dosage form, then permeate the walls ofgastrointestinal tract before entering the bloodstream.

Orally-dissolving oral dosage forms also exist, but suffer from theirown drawbacks. They often provide an unreliably measurable dose ofmelatonin to the patient. The dose a patient absorbs can vary even whenthe same product is administered to the same patient or differentpatients.

BRIEF SUMMARY

The melatonin compositions described here are formulated to delivermelatonin to the mouth where it is absorbed by the body through the oralmucosa. To overcome the high pH of the saliva and tongue, thecomposition includes an acidifying agent that lowers the pH inside themouth, which enhances the oral solubility of melatonin. By being moresoluble in the mouth, melatonin may more readily pass through the oralmucosa and into the bloodstream. This may make the melatonin dose in theplasma more predictable when compared to convention orally-dissolvingmelatonin dosage forms.

A first example of the composition includes a pharmaceutical dosage formconfigured to dinsintegrate in saliva and maintain a pH of 4 or lesswithin the saliva during the time the dosage form is dissolving therein.The dosage form may include a therapeutically effective amount ofmelatonin in a carrier matrix, a disintegrant, and a sufficient amountof acid to impart the pH to the saliva. The amount of disintegrant issufficient to cause the dosage form to completely dinsintegrate in thesaliva within ten minutes from contacting the saliva.

The dosage form of this first example may be at least one of asublingual tablet, a buccal tablet, and a polymer strip.

When the dosage form of this first example is a buccal or sublingualtablet, it may be at least 20% w/w of the acid.

When the dosage form of this first example is a polymer strip, it may beat least 5% w/w of the acid.

When the dosage form of this first example is a buccal tablet, it may beat least 6% w/w disintegrant.

When the dosage form of this first example is a sublingual tablet, itmay be at least 15% w/w disintegrant.

The therapeutically effective amount of melatonin in this first examplemay be 0.2 mg to 20 mg.

The dosage form of this first example may be a tablet and the carriermatrix includes microcrystalline cellulose as at least 45% w/w of thedosage form, the acid as at least 20% w/w of the dosage form, and thedisintegrant as at least 6% w/w of the dosage form.

The acid in this first example may be a carboxylic acid such as citricacid.

In the dosage form of this first example, the amount of disintegrant maybe sufficient to cause the dosage form to completely dinsintegrate inthe saliva within 2 minutes from contacting the saliva.

In the dosage form of this first example, the amount of disintegrant maybe sufficient to cause the dosage form to completely dinsintegrate inthe saliva within 1 minute from contacting the saliva.

A second example of the composition includes a pharmaceutical dosageform configured to dinsintegrate in saliva and maintain a pH of 4 orless within the saliva during the time the dosage form is dissolvingtherein. The dosage form includes 0.2% w/w to 20% w/w melatonin intherapeutically effective amount; a carrier matrix including 45% w/w to68% w/w filler, and 6% w/w to 20% w/w disintegrant. The amount ofdisintegrant is sufficient to cause the dosage form to completelydinsintegrate in the saliva within ten minutes from contacting thesaliva. The dosage form also includes 20% w/w to 30% w/w acid. Theamount of acid is effective to impart the pH to the saliva.

The dosage form of this second example may be at least one of asublingual or buccal tablet.

In the dosage form of this second example, the disintegrant may includecrospovidone, the filler may include microcrystalline cellulose, and theacid may include citric acid.

When the dosage form of this second example is a sublingual tablet, thedisintegrant may be at least 15% w/w of the dosage form.

The therapeutically effective amount of melatonin in this second examplemay be 0.2 mg to 20 mg.

The acid in this second example may be a carboxylic acid such as citricacid.

In the dosage form of this second example, the amount of disintegrantmay be sufficient to cause the dosage form to completely dinsintegratein the saliva within 2 minutes from contacting the saliva.

In the dosage form of this second example, the amount of disintegrantmay be sufficient to cause the dosage form to completely dinsintegratein the saliva within 1 minutes from contacting the saliva.

A third example of the composition includes an oral strip pharmaceuticaldosage form configured to dinsintegrate in saliva and maintain a pH of 4or less within the saliva during the time the strip is dissolvingtherein. The dosage form includes 0.2% w/w to 20% w/w melatonin intherapeutically effective amount; a carrier matrix including 45% w/w to90% w/w water soluble polymer, 1% w/w to 20% w/w plasticizer; and 5% w/wto 20% w/w acid. The amount of acid is effective to impart the pH to thesaliva.

In the composition of this third example, the strip has a thickness of 1mm or less.

In the composition of this third example, dosage form may furtherinclude 20% w/w to 30 w/w surfactant.

In the composition of this third example, the water soluble polymer maybe 50% w/w to 70% w/w of the dosage form.

In the composition of this third example, the acid may be 8% w/w to 12%w/w of the dosage form.

In the composition of this third example, the acid may be a carboxylicacid such as citric acid.

Any of the first second and third examples of the composition describedabove may be used in a method of treatment. An example of such a methodincludes administering a composition comprising a pharmaceutical dosageform to a subject in need thereof. The pharmaceutical dosage formdinsintegrates in the subject's saliva while maintaining a pH of 4 orless within the saliva during the time the dosage form is dissolving.The dosage form includes a therapeutically effective amount of melatoninin a carrier matrix, a disintegrant, and a sufficient amount of acid toimpart the pH to the saliva. The amount of disintegrant is sufficient tocause the dosage form to completely dinsintegrate in the saliva withinten minutes from contacting the saliva.

The dosage from in this method may be at least one of a sublingualtablet, a buccal tablet, and a polymer strip.

The dosage form in this method may be a buccal or sublingual tablet,which is at least 20% w/w of the acid.

The dosage form in this method may be is a polymer strip, which is atleast 5% w/w of the acid.

The dosage form in this method may be a buccal tablet, which is at least6% w/w disintegrant.

The dosage form in this method may be a sublingual tablet, which is atleast 15% w/w disintegrant.

In this method, the therapeutically effective amount of melatonin may be0.2 mg to 20 mg.

The dosage form in this method may be a tablet and the carrier matrixmay include microcrystalline cellulose as at least 45% w/w of the dosageform, the acid as at least 20% w/w of the dosage form, and thedisintegrant as at least 6% w/w of the dosage form.

In this method, administering may occur within 30 minutes of the timethe subject desires to fall asleep.

In this method, administering may occur at night after the subject hasawoken from sleep and desires to fall back asleep.

In this method, the acid may be a carboxylic acid such as citric acid.

In this method, the amount of disintegrant may be sufficient to causethe dosage form to completely dinsintegrate in the saliva within 2minutes from contacting the saliva.

In this method, the amount of disintegrant may be sufficient to causethe dosage form to completely dinsintegrate in the saliva within 1minute from contacting the saliva.

DESCRIPTION OF EXAMPLE EMBODIMENTS

A problem with administering melatonin via an orally-releasing dosageform is that the pH of the mouth, especially the tongue coating, is toohigh. The pH of the saliva has been reported to be about 6.4-6.6 and thepH of the tongue coating has been reported to be about 7.1-7.4. SeeTollentino et al, Journal of Applied Oral Science, 19(2), pg. 90 (2011).Because melatonin is sparingly soluble at near neutral and basic pHs,the melatonin in an orally-releasing dosage form might not be solubleenough to be available for absorption via the oral mucosa, especiallythe sublingual or buccal mucosa.

The compositions described here overcome this problem. They includemelatonin in an oral mucosal delivery dosage form adapted to release themelatonin in the mouth where it can then be absorbed through the oralmucosa and an acidifying agent that imparts a low enough pH to thedosage form and the saliva in the vicinity of the dosage form to renderthe melatonin water soluble.

The compositions are formulated to deliver melatonin across the oralmucosa. The oral mucosa include, for example, the buccal mucosa andsublingual mucosa. Depending on the formulation, different examples ofthe composition may be targeted for buccal and/or sublingual delivery.

The sublingual mucosa is the most permeable oral mucus membrane and isan established route of oral administration. The buccal mucosa is lesspermeable than the sublingual mucosa, but is also an established routeof oral administration. Some examples of sublingual and buccal dosageforms include, dissolving tablets, lozenges, candy, strips, and softcapsules. Respectively, sublingual and buccal dosage forms yield a highsublingual/buccal concentration of melatonin so that melatonin can beabsorbed across the sublingual/buccal mucosa. Delivery of activeingredients via the sublingual or buccal mucosa is known to produce arapid onset of action of the active ingredient and bypasses thegastrointestinal tract.

There are many different types of orally dissolving dosage forms forabsorption of active ingredients by the oral mucosa. Some examples ofthe oral mucosal dosage forms include orally dissolving tablets,chewable tablets, dissolving granules, lozenges, strips, chewing gums,and the like. Although certain particular examples of these dosage formsare described herein, it should be understood that the scope of thisdisclosure includes preparing the composition in any of these dosageforms and like dosage forms that are not mentioned here in detail.

An orally dissolving tablet or an orally disintegrating tablet isformulated to dinsintegrate in the mouth rather than being swallowedwhole. One of the advantages of such a dosage form is that it can beadministered without water. Saliva from the subject's mouth causes thetablet to dinsintegrate. The dinsintegrated contents may he held in thesubject's mouth without swallowing for a specified time while themelatonin absorbs into the subject's oral mucosa.

Orally dissolving tablets may be prepared by blending the ingredientstogether and compressing them into a tablet. The tablet may have anydesired shape, but is often disc-shaped and is small enough to sit in acavity in the mouth adjacent the oral mucosa being targeted fordelivery.

A sublingual tablet is intended to be held under the tongue withoutswallowing for a time while the tablet dinsintegrates and the melatoninis absorbed through the sublingual mucosa. Accordingly, a sublingualtablet should have a size and shape that is comfortable for placementunder the tongue.

A buccal tablet is intended to be held between the teeth and the cheekwithout swallowing for a time while the tablet dinsintegrates and themelatonin is absorbed through the buccal mucosa. Accordingly, a buccaltablet should have a size and shape that is comfortable for placementbetween the teeth and cheek.

The tablet, regardless of its intended target for absorption, may beplaced directly onto the tongue where it can dissolve and the melatoninbe absorbed through the oral mucosa generally.

In another example, the tablet is a chewable tablet that is chewed bythe patient. The chewable tablet may be administered by placing it inthe patient's mouth. The chewable tablet can then be moved around withinthe mouth during chewing. The chewed product can sometimes be packedbetween the gums and the cheeks or underneath the tongue.

A polymer strip, orally dissolving strip, or oral thin film dosage formis a thin polymer film, often less than 1 mm thick, that adheres to theskin inside the mouth and rapidly dinsintegrates thereon. The stripincludes a hydrophilic polymer carrier matrix that contains themelatonin. The strip does not require water for administration since itwill dinsintegrate on contact with saliva.

As compared to a tablet, the strip is flexible and requires lesspackaging space. The strip also provides a larger surface area forcontacting the skin compared to tablets. The surface area may be, forexample 1-20 cm².

The strip is intended to be placed on the skin inside the mouth, oftenon the tongue, under the tongue, or cheek, and held without swallowingfor a time while the strip dinsintegrates and the melatonin is absorbedthrough the oral mucosa.

The polymer strip dosage form may be prepared using a conventionalapproach such as solvent casting, hot-melt extrusion, semisolid casting,sold dispersion extrusion, and rolling.

The composition may be formulated in such a way that the dosage formcompletely disintegrates within the mouth in about 15 minutes, about 10minutes, about 5 minutes, about 3 minutes, about 2 minutes, or about 1minute following administration to the mouth and contact with thesaliva.

The acidifying agent lowers the pH inside the mouth to temporarily lowerthe local pH of the saliva and/or the tongue coating to maintainmelatonin in a soluble form at the mucosa interfaces for absorption. Theacidifying agent lowers the pH of saliva and/or the tongue coating to apH of about 4 or less, about 1 to about 4, about 2 to about 4, or about3 to about 4. The pH may be maintained at the desired level duringsubstantially the entire time from when the composition begins todinsintegrate in the saliva to when it is completely dinsintegrated inthe saliva. In a particular example, the pH is maintained at 3.3 orbelow, which is below the pK_(a) of melatonin.

The composition is configured to dinsintegrate in saliva and maintain apH of 4 or less within the saliva during the time the dosage form isdissolving therein. In certain examples the pH is maintained at 3.3 orless or from 2 to 3.3. The phrase “during the time the dosage form isdissolving therein” refers to the time from when the dosage form hasdinsintegrated enough in saliva to create a local pH within the desiredrange to make the melatonin in the dosage form soluble. The amount ofacidifying agent in the composition is selected to provide the desiredpH.

The acidifying agent may include at least one organic and/or inorganicacid, including carboxylic acids such as citric acid, succinic acid,tartaric acid, acetic acid, or the like; and phosphoric acid,hydrochloric acid, or the like.

The acidifying agent may include at least one buffering agent such as aconjugate base of the acid(s) used in the acidifying agent. Examplesinclude citrate salts such as monosodium citrate, and phosphate saltssuch as phosphoric acid monopotassium salts, and the like.

The ingredients of the composition are combined in a carrier matrix thatprovides the physical structure of the dosage form. The composition ofthe carrier matrix will vary depending on the type of dosage form beingused.

For tablet type dosage forms and the like, the majority of the carriermatrix may be a pharmaceutical filler or bulking agent. Examples of suchfillers include, but are not limited to, sucrose, lactose, mannitol,dicalcium phosphate dihydrate, starch, cellulosic materials,microcrystalline cellulose, and the like.

For tablet type dosage forms and the like, carrier matrix may alsoinclude a disintegrant. The disintegrant is effective to speed the rateof disintegration of the dosage form in the mouth, often by swelling andcausing the dosage form to fall apart. Some examples of disintegrantsinclude, but are not limited to, croscarmellose sodium, crospovidone,sodium starch glycolate, and the like. The disintegrant may also becalled a superdisintegrant.

The composition may include a binder that helps adhere the components ofthe dosage form together. Examples of binders include, but are notlimited to, sugars such as glucose, lactose, dextrose, fructose,sucrose, and the like; sugar alcohols such as mannitol, sorbitol, andxylitol and the like; gums such as acacia gum, xanthan gum, guar gum,locust bean gum, and the like; starch; cellulose, microcrystallinecellulose, polyvinylpyrrolidone, alginate, gelatin, methylcellulose,ethylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose,polyacrylic acid, polyethylene glycol, and other possibilities.

For polymer strip type dosage forms, the carrier matrix may include awater soluble polymer. Examples of water soluble polymers include, butare not limited to, polyethylene oxide, maltodextrin, hydroxypropylmethylcellulose, hydroxypropyl cellulose, starch, modified starch,pullan, gelatin, carboxymethyl cellulose, and the like.

For polymer strip type dosage forms, the carrier matrix may also includea plasticizer, typically in an amount less than the polymer. Theplasticizer is effective to soften the polymer and render it moreflexible that it would otherwise be without the plasticizer. Examples ofplasticizers include, but are not limited to, glycerol, glycerin,polyethylene glycols, propylene glycol, sorbitol sorbitan, and the like.

The composition may include a thickener. Examples of thickeners include,but are not limited to, gum bases, and the like, gums such as acaciagum, xanthan gum, guar gum, locust bean gum, carrageenan, and the like.A thickener may be especially useful in polymer strip dosage forms.

The composition may include a surfactant. Examples of surfactantsinclude, but are not limited to, sodium lauryl sulfate, benzalkoniumchloride, benzthonium chloride, polysorbate 20, cetearyl alcohol,glyceryl surfactants, cetyl pyridinium chloride, and the like.

The composition may include a mucoadhesive agent such as a mucoadhesivepolymer to enhance adhesion of the dosage form to the oral mucosa, whichmight also improve retention at the desired delivery site. Examples ofmucoadhesive agents include, but are not limited to, alginates, lectins,carageenans, pectins, cellulosic materials, and the like.

The composition may include a sweetener to enhance the taste of thedosage form. Sweeteners include both natural and artificial sweetenersincluding, but not limited to, sucralose, aspartame, saccharin, stevia,acesulfame potassium, sugar alcohols such as glycerol, sorbitol,maltitol, mannitol, and erythritol, isomalt, maltodextrin, naturalsugars, and the like.

The composition may include a flavor such as a natural or artificialflavor. The composition may also include a coloring agent to give thedosage form a desirable color.

Several more particular examples of the composition will now bedescribed. These examples are presented as percent by weight (% w/w) ofthe specified ingredient relative to the dosage form. Any combination ofthe ingredients in the % w/w listed below may be employed in any of theexample compositions discussed herein.

In some of the compositions, melatonin may be 0.1%-5% w/w; 0.1%-2% w/w,0.1% to 1% w/w, or 0.2%-0.7% w/w of the composition.

In some of the compositions, the acidifying agent may be 0.5%-30% w/w,1%-25% w/w, 25%-30% w/w, 8%-12% w/w, 1%-15% w/w, 5%-15% w/w, 2%-10% w/w,7%-15% w/w, 6%40% w/w, or 7%-9% w/w of the composition. The amount ofacidifying agent is effective to impart the pH discussed herein to thedosage form and saliva in the vicinity of the dosage to render melatoninsoluble in the saliva.

Three more particular examples of possible dosage forms are nowdiscussed. It should be understood that all three of these dosage formexamples are examples of the first example of the composition discussedabove.

TABLE 1 Examples of possible amounts of certain ingredients in a dosageform Ingredient % w/w % w/w % w/w % w/w melatonin 0.2-2  0.5-1.5 0.8-1.2about 1   disintegrant 15-20 16-19 16-18 about 17.5 acidifying agent20-30 22-29 25-29 about 27.5 filler 46-63 50-60 52-58 about 54  

Table 1 provides several examples of exemplary % w/w ranges of certainprimary ingredients in a dosage form such as a sublingual tablet. The %w/w balance of the dosage form of Table 1 may include a flow agent, asweetener, a flavor, and a color, for example. The flow agent may be0.05% w/w to 0.2% w/w or about 0.1% w/w of the dosage form. The flavormay be 0.1% w/w to 5% w/w or about 2.5% w/w of the dosage form. Thesweetener may be 0.1% w/w to 5% w/w or about 2.5% w/w of the dosageform. The color may be 0.25% w/w to 0.75% w/w or about 0.5% w/w of thedosage form.

TABLE 2 Examples of possible amounts of certain ingredients in a dosageform Ingredient % w/w % w/w % w/w % w/w melatonin 0.2-2  0.5-1.5 0.8-1.2about 1 disintegrant  6-10 7-9 7.5-8.5 about 8 acidifying agent 20-3022-29 25-29   about 27.5 filler 50-68 55-61 56-60  about 58

Table 2 provides several examples of exemplary % w/w ranges of certainprimary ingredients in a dosage form such as a buccal tablet. The % w/wbalance of the dosage form of Table 2 may include a flow agent, asweetener, a flavor, and a color, for example. The flow agent may be0.05% w/w to 0.2% w/w or about 0.1% w/w of the dosage form. The flavormay be 0.1% w/w to 5% w/w or about 2.5% w/w of the dosage form. Thesweetener may be 0.1% w/w to 5% w/w or about 2.5% w/w of the dosageform. The color may be 0.25% w/w to 0.75% w/w or about 0.5% w/w of thedosage form.

TABLE 3 Examples of possible amounts of certain ingredients in a dosageform Ingredient % w/w % w/w % w/w % w/w melatonin 0.05-2   0.25-1.5 0.25-0.75 about 0.5 carrier matrix polymer 45-90 55-65 58-62 about 60 acidifying agent  5-20  7-13  8-12  about 10.5

Table 3 provides several examples of exemplary % w/w ranges of certainprimary ingredients in a dosage form such as a polymer strip. The % w/wbalance of the dosage form of Table 3 may include a plasticizer, asurfactant, a thickener, a sweetener, a flavor, and a color, forexample. The plasticizer may be 1% w/w to 20% w/w or about 10% w/w ofthe dosage form. The surfactant may be % w/w to 20% w/w or about 10% w/wof the dosage form. The thickener may be 2.5% w/w to 5% w/w or about3.5% w/w of the dosage form. The flavor may be 0.1% w/w to 5% w/w orabout 2.5% w/w of the dosage form. The sweetener may be 0.1% w/w to 5%w/w or about 2.5% w/w of the dosage form. The color may be 0.25% w/w to0.75% w/w or about 0.5% w/w of the dosage form.

For any of the examples presented in Tables 1-3 the specified ingredientmay be, for example, one or more of the ingredients in each classdiscussed in previous paragraphs.

The composition may be administered orally to a human or animal patientin a therapeutically effective amount, which is an amount that issufficient to provide a therapeutic benefit affecting a disease orcondition in the body.

A therapeutically effective amount of melatonin may be, for example:0.01-1,000 mg, 0.01-500 mg, 0.01-100 mg, 0.01 to 50 mg, 0.01-25 mg,0.01-10 mg, 0.01-5 mg. The therapeutically effective amount can varyoutside of these ranges as well. The weight in mg is often calibrated tothe body weight of the patient in kg, thus these example doses may alsobe written in terms of mg/kg of body weight per day.

In practice, the therapeutically effective amount may vary depending onnumerous factors associated with the patient, including age, weight,height, severity of the condition, administration technique, and otherfactors. The therapeutically effective amount administered to a patientmay be determined by medical personnel taking into account the relevantcircumstances.

The therapeutically effective amount may be determined or predicted fromempirical evidence. Specific dosages may vary according to numerousfactors and may be initially determined on the basis of experimentation.

The composition may be administered as a single dose or as part of adosage regimen. For a dosage regimen, the therapeutically effectiveamount is adjustable dose to dose to provide a desired therapeuticresponse.

Multiple doses may be administered at a predetermined time interval andsubsequent doses may be proportionally reduced or increased, dependingon the situation.

The composition may be used to treat many physiological conditions forwhich melatonin provides a therapeutic benefit. In a particular methodof use, the composition is used to provide an acute dose of melatonin tothe patient at or near bedtime or when the patient awakes and desires tofall back asleep. The oral mucosal dosage form will provide a fasteronset of melatonin's sleep aid effects compared to conventionalmelatonin dosage forms delivered through gastrointestinal tract.

An example method of treatment includes administering to a patient inneed thereof a therapeutically effective composition includingmelatonin, a pharmaceutical carrier, and an amount of acidifying agenteffective to lower the pH of a tongue coating to a pH of 4 or less. Thecomposition may be administered by the patient, a physician, or thepatient's caretaker by placing the composition in the patient's mouthand holding it in the mouth without swallowing the contents. In such amethod, the composition is particularly advantageous for administrationif the patient awakes in the middle of the night after being asleepand/or to help the patient initially fall asleep at bedtime.Administering may occur, for example, within 30 minutes of the time thesubject desires to fall asleep and/or at night after the subject hasawoken from sleep and desires to fall back asleep.

When administered, the composition is introduced to the patient's mouthand held in the mouth while the dosage form disintegrates. In somecases, the dosage form may be placed on top of the tongue while itdisintegrates. In other cases it may be placed against the mucousmembrane being targeted for delivery, such as the sublingual and/orbuccal mucosa, and held there while it disintegrates.

EXAMPLES

The following examples are provided to illustrate aspects of certainexamples of the composition. The scope of possible examples is notlimited to the details of these examples

Example 1 Tablet for Sublingual Delivery

Table 4 provides an example of a sublingual tablet dosage form and itsingredients in a particular example and a range of possible amounts inother possible examples.

TABLE 4 Sublingual tablet formulation Range- Range- Amount Low HighIngredient (mg/gm) (mg/gm) (mg/gm) Melatonin 10 .2 20 disintegrant (e.g.croscarmellose 175 150 200 sodium) Citric acid 275 200 300Filler/stabilizing agent (e.g. micro- 539 460 630 crystalline cellulose)Flow agent (e.g. magnesium stearate) 1 .5 2 Flavoring agents (e.g.menthol, 25 1 50 lavender) Sweetening agents (e.g. aspartame, 25 1 50sorbitol) Coloring agents (e.g. titanium 5 2.5 7.5 dioxide, FD&Ccoloring pigments) TOTAL 1000

The sublingual tablet is a small, flat tablet that is administeredorally to be placed under the tongue. At which point, the tablet beginsto dinsintegrate rapidly, allow the melatonin to be absorbed directlythrough the oral mucosa; bypassing first pass metabolism and beingdistributed directly into the venous blood supply.

The manufacture of the tablet in this example involves the dry blendingand compression of the melatonin and excipients into a flat disc. Thecitric acid acts to control the pH to allow for transdermal delivery,and to stimulate saliva to help with dissolution and absorption. Othercomponents include a high concentration of a disintegrant, a tabletfiller, a powder flowing agent, as well as flavoring, sweetening andcoloring agents.

Example 2 Tablet for Buccal Delivery

Table 5 provides an example of a buccal tablet dosage form and itsingredients in a particular example and a range of possible amounts inother possible examples.

TABLE 5 Buccal tablet formulation Range- Range- Amount Low HighIngredient (mg/gm) (mg/gm) (mg/gm) Melatonin 10 .2 20 disintegrant (e.g.croscarmellose 80 60 100 sodium) Citric acid 275 200 300Filler/stabilizing agent (e.g. micro- 579 500 675 crystalline cellulose)Flow agent (e.g. magnesium stearate) 1 .5 2 Flavoring agents (e.g.menthol, 25 1 50 lavender) Sweetening agents (e.g. aspartame, 25 1 50sorbitol) Coloring agents (e.g. titanium 5 2.5 7.5 dioxide, FD&Ccoloring pigments) TOTAL 1000

A buccal tablet is a small, flat tablet that is administered orally tobe placed between the check and the gums (buccal cavity). At whichpoint, the tablet begins to dinsintegrate rapidly, allow the melatoninto be absorbed directly through the buccal mucosa; bypassing first passmetabolism and being distributed directly into the venous blood supply.

The manufacture of the tablet in this example involves the dry blendingand compression of the melatonin and excipients into a flat disc. Thecitric acid acts to control the pH to allow for transdermal delivery,and to stimulate saliva to help with dissolution and absorption. Othercomponents include a disintegrant, a tablet filler agent, a powderflowing agent, as well as flavoring, sweetening and coloring agents.

Example 3 Oral Thin Film

Table 6 provides an example of a polymer strip or oral thin film dosageform and its ingredients in a particular example and a range of possibleamounts in other possible examples.

TABLE 6 Polymer strip formulation Range- Range- Amount Low HighIngredient (mg/gm) (mg/gm) (mg/gm) Melatonin 5 0.5 20 Water solublepolymer (e.g. polyeth- 600 450 900 ylene oxide, maltodextrin, hydroxypropyl methyl cellulose, hydroxy propyl cellulose, starch or modifiedstarch, pullulan, gelatin, carboxy methyl cellulose) Plasticizer (e.g.glycerol, propylene 100 10 200 glycol) Citric acid 105 50 200Stabilizing/thickening agents (e.g. 35 25 50 xanthan gum, locust beangum, carragenan) Surfactant (e.g. sodium lauryl sulfate, 100 10 200benzalkonium chloride, benzthonium chloride, tween) Flavoring agents(e.g. menthol, 25 1 50 lavender) Sweetening agents (e.g. aspartame, 25 150 sorbitol) Coloring agents (e.g. titanium 5 2.5 7.5 dioxide, FD&Ccoloring pigments) TOTAL 1000

A polymer strip is a thin strip that is designed to dinsintegratequickly under the tongue. Similar to the sublingual tablet, it isabsorbed directly through the oral mucosa; bypassing first passmetabolism and being distributed directly into the venous blood supply.

The manufacture of this film is by hot melt extrusion. In this process,the solid materials including melatonin and excipients are loaded into ahopper, conveyed, mixed and melted by a ram or screw extruder. Theextrudate is then deposited into a die of desirable form.

The citric acid acts to control the pH to allow for transdermaldelivery, and to stimulate saliva to help with dissolution andabsorption. Other components include water soluble polymer to act as thebulk of the film, a plasticizer to allow for film flexibility, astabilizing agent, a surfactant, a flavoring agent, a sweetening agent,and a coloring agent.

This disclosure has described example embodiments, but not all possibleembodiments of the compositions or associated methods. Where aparticular feature is disclosed in the context of a particular exampleembodiment, that feature can also be used, to the extent possible, incombination with and/or in the context of other embodiments. Thecomposition and related methods may be embodied in many different formsand should not be construed as limited to only the examples describedhere.

The compositions and methods are not limited only to the detailsdescribed in connection with the example embodiments. There are numerousvariations and modification of the compositions and methods that may bemade without departing from the scope of what is claimed.

That which is claimed is:
 1. A composition comprising a pharmaceuticaldosage form configured to disintegrate in oral saliva and maintain a pHof 4 or less within the saliva during the time the dosage form isdissolving therein, the dosage form including a therapeuticallyeffective amount of melatonin in a carrier matrix, a disintegrant, and asufficient amount of acid to impart the pH to the saliva, the amount ofdisintegrant being sufficient to cause the dosage form to completelydisintegrate in the saliva, wherein the dosage form is at least one of asublingual tablet and a buccal tablet within ten minutes from contactingthe saliva.
 2. The composition of claim 1, wherein the dosage form is atleast 20% w/w of the acid.
 3. The composition of claim 1, wherein thedosage form is a buccal tablet, that is at least 6% w/w disintegrant. 4.The composition of claim 1, wherein the dosage form is a sublingualtablet, that is at least 15% w/w disintegrant.
 5. The composition ofclaim 1, wherein the therapeutically effective amount of melatonin is0.2 mg to 20 mg.
 6. The composition of claim 1, wherein the dosage formis a tablet and the carrier matrix includes microcrystalline cellulosein at least 45% w/w of the dosage form, the acid in at least 20% w/w ofthe dosage form, and the disintegrant in at least 6% w/w of the dosageform.
 7. The composition of claim 1, wherein the acid is a carboxylicacid.
 8. The composition of claim 1, wherein the acid is citric acid. 9.The composition of claim 1, wherein the amount of disintegrant issufficient to cause the dosage form to completely disintegrate in thesaliva within 2 minutes from contacting the saliva.
 10. The compositionof claim 1, wherein the amount of disintegrant is sufficient to causethe dosage form to completely disintegrate in the saliva within 1 minutefrom contacting the saliva.
 11. A method comprising administering acomposition comprising a pharmaceutical dosage form to a subject in needthereof, the pharmaceutical dosage form dissolving in the subject'ssaliva while maintaining a pH of 4 or less within the saliva during thetime the dosage form is dissolving, the dosage form including atherapeutically effective amount of melatonin in a carrier matrix, adisintegrant, and a sufficient amount of acid to impart the pH to thesaliva, the amount of disintegrant being sufficient to cause the dosageform to completely disintegrate in the saliva within ten minutes fromcontacting the saliva, wherein the dosage form is at least one of asublingual tablet and a buccal tablet.
 12. The method of claim 11,wherein the dosage form is at least 20% w/w of the acid.
 13. The methodof claim 11, wherein the dosage form is a buccal tablet, that is atleast 6% w/w disintegrant.
 14. The method of claim 11, wherein thedosage form is a sublingual tablet, that is at least 15% w/wdisintegrant.
 15. The method of claim 11, wherein the therapeuticallyeffective amount of melatonin is 0.2 mg to 20 mg.
 16. The method ofclaim 11, wherein the carrier matrix includes microcrystalline cellulosein at least 45% w/w of the dosage form, the acid in at least 20% w/w ofthe dosage form, and the disintegrant in at least 6% w/w of the dosageform.
 17. The method of claim 11, wherein administering occurs within 30minutes of the time the subject desires to fall asleep.
 18. The methodof claim 11, wherein administering occurs at night after the subject hasawoken from sleep and desires to fall back asleep.
 19. The method ofclaim 11, wherein the acid is a carboxylic acid.
 20. The method of claim11, wherein the acid is citric acid.
 21. The method of claim 11, whereinthe amount of disintegrant is sufficient to cause the dosage form tocompletely disintegrate in the saliva within 2 minutes from contactingthe saliva.
 22. The method of claim 11, wherein the amount ofdisintegrant is sufficient to cause the dosage form to completelydisintegrate in the saliva within 1 minute from contacting the saliva.23. A composition comprising: a pharmaceutical dosage form configured todisintegrate in saliva and maintain a pH of 4 or less within the salivaduring the time the dosage form is dissolving therein, the dosage formincluding: 2% w/w to 20% w/w melatonin in a therapeutically effectiveamount; a carrier matrix including 45% w/w to 68% w/w filler, 6% w/w to20% w/w disintegrant, the amount of disintegrant being sufficient tocause the dosage form to completely disintegrate in the saliva withinten minutes from contacting the saliva; and 20% w/w to 30% w/w acid, theamount of acid being effective to impart the pH to the saliva, whereinthe dosage form is at least one of a sublingual tablet and a buccaltablet.
 24. The composition of claim 23, wherein the disintegrantincludes crospovidone, the filler includes microcrystalline cellulose,and the acid includes citric acid.
 25. The composition of claim 23,wherein the dosage form is a sublingual tablet and the disintegrant ispresent in at least 15% w/w of the dosage form.
 26. The composition ofclaim 23, wherein the therapeutically effective amount of melatonin is0.2 mg to 20 mg.
 27. The composition of claim 23, wherein the acid is acarboxylic acid.
 28. The composition of claim 23, wherein the acid iscitric acid.
 29. The composition of claim 23, wherein the amount ofdisintegrant is sufficient to cause the dosage form to completelydisintegrate in the saliva within 2 minutes from contacting the saliva.30. The composition of claim 23, wherein the amount of disintegrant issufficient to cause the dosage form to completely disintegrate in thesaliva within 1 minute from contacting the saliva.